Agnieszka Zahorodna

5-HT7 receptors increase the excitability of rat hippocampal CA1 pyramidal neurons

In the CA1 area of rat hippocampal slices, a combined application of 5-CT, a potent 5-HT(1A) and 5-HT(7) receptor agonist, and WAY 100635, a selective 5-HT(1A) receptor antagonist, resulted in a reversible increase of the CA1 extracellular population spike amplitude. In whole-cell recording from identified pyramidal neurons, the effects of 5-CT applied in the presence of WAY 100635 involved a reduction of the slow afterhyperpolarization (sAHP) and the frequency adaptation of action potential firing, which could be blocked by a specific 5-HT(7) receptor antagonist SB 269970. The results indicate that the activation of 5-HT(7) receptors increases the excitability of hippocampal CA1 pyramidal cells.

An antidepressant-induced decrease in the responsiveness of hippocampal neurons to group I metabotropic glutamate receptor activation

Imipramine, a serotonin and noradrenaline uptake inhibitor, is the prototypical tricyclic antidepressant. The effects of imipramine on neuronal responsiveness to the group I glutamate metabotropic (mGlu) receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) were studied ex vivo, in the CA1 area of rat hippocampus, using extracellular and intracellular recording. DHPG increased the population spike amplitude, depolarized CA1 cells and decreased the slow afterhyperpolarization. Imipramine (20 microM) administered acutely in vitro did not change the effect of DHPG on population spikes. Repeated treatment with imipramine (10 mg/kg, twice daily, for 14 days) significantly attenuated the enhancing effect of DHPG (2.5 and 5 microM) on population spikes, as well as the DHPG-induced depolarization and the decrease in the slow afterhyperpolarization. Repeated treatment with imipramine had no effect on passive or active membrane properties of CA1 pyramidal cells. The results of the time-course experiment demonstrated that the imipramine-induced decrease in the responsiveness of CA1 cells to DHPG was apparent after a 7-day treatment; there was a further decrease after 14 days of treatment to a level which was not changed by longer (21-day) administration of imipramine. The attenuation of neuronal responsiveness to DHPG induced by a 14-day treatment was still detectable 7 days after imipramine withdrawal. It is concluded that repeated treatment with imipramine induces a decrease in the responsiveness of rat CA1 hippocampal neurons to group I mGlu receptor activation with a time course which correlates with the delayed onset of the therapeutic effect of antidepressants in humans. This suggests that alterations in mGlu receptors may contribute to antidepressant efficacy.

Comparison of the effects of 5-HT1A and 5-HT4 receptor activation on field potentials and epileptiform activity in rat hippocampus

Abstract. The effects of serotonin (5-HT) as well as 5-HT1A and 5-HT4 receptor agonists, (±)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) and zacopride, respectively, on population spikes evoked by electrical stimulation and on spontaneous epileptiform activity were investigated in CA1 area of hippocampal slices. Spontaneous epileptiform activity was recorded from slice in a nominally Mg2+-free medium. While 5-HT application resulted in a decrease of population spikes evoked in standard incubation conditions, in accordance with earlier studies, it exerted two opposite effects on epileptiform activity. The early inhibitory effect was mimicked by 8-OH-DPAT while the later, excitatory, by zacopride. The application of 8-OH-DPAT decreased, and that of zacopride increased, the amplitude of population spikes. A comparison of the dose-dependence of the excitatory and inhibitory effects of serotonergic agonists on the amplitude of the population spike and on the frequency of epileptiform discharges indicated that the latter is a more sensitive measure of the activation of 5-HT1A and 5-HT4 receptors than the former. Thus, spontaneous epileptiform activity recorded in a nominally Mg2+-free slice medium represents a convenient model for investigation of hippocampal neuronal reactivity to the activation of various 5-HT receptor subtypes.

Imipramine but not 5-HT1A receptor agonists or neuroleptics induces adaptive changes in hippocampal 5-HT1A and 5-HT4 receptors

It has been reported that the treatment with a tricyclic antidepressant imipramine induces an increase in the sensitivity of 5-HT(1A) receptors and a decrease in the sensitivity of 5-HT(4) receptors in the rat hippocampus. 5-HT(1A) receptor agonists and neuroleptics also affect 5-HT(1A) receptors in different brain areas; therefore, it was of interest to compare their effects on hippocampal 5-HT receptors with the influence of the well-established antidepressant imipramine. We studied the effects of repeated treatment with imipramine, the 5-HT(1A) receptor agonists 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, and the neuroleptics haloperidol and clozapine on the sensitivity of rat hippocampal CA1 neurons to 5-HT(1A)- and 5-HT(4) receptor activation. Imipramine was administered for 21 days (10 mg/kg p.o., twice daily), 8-OH-DPAT for 7 days (1 mg/kg s.c., twice daily) and buspirone for 21 days (5 mg/kg s.c., twice daily). The rats received haloperidol (1 mg/kg) and clozapine (30 mg/kg) for 6 weeks in drinking water. Hippocampal slices were prepared 2 days after the last treatment with imipramine, 8-OH-DPAT or buspirone, and 5 days after the last treatment with the neuroleptics. Using an extracellular in vitro recording, we studied changes in the amplitude of stimulation-evoked population spikes, induced by 5-HT, 8-OH-DPAT and the 5-HT(4) receptor agonist zacopride. Activation of 5-HT(1A) receptors decreased, while activation of 5-HT(4) receptors increased the amplitude of population spikes. Imipramine significantly enhanced the inhibitory effects of 5-HT and 8-OH-DPAT, and attenuated the excitatory effect of zacopride. No other treatment used in the present study changed the sensitivity of hippocampal CA1 neurons to 5-HT(1A) and 5-HT(4) receptors activation. These findings indicate that adaptive changes in the sensitivity of hippocampal neurons to 5-HT(1A) and 5-HT(4) receptors agonists are specific to imipramine and may thus-at least partly-mediate its effects.

Imipramine treatment ameliorates corticosterone-induced alterations in the effects of 5-HT1A and 5-HT4 receptor activation in the CA1 area of rat hippocampus

This study tested whether imipramine reverses adaptive modifications in the function of hippocampal 5-HT1A and 5-HT4 receptors induced by repetitive administration of corticosterone. Rats received corticosterone for 1 or 3 weeks or imipramine for 2 weeks. The fourth experimental group was treated with corticosterone for 3 weeks and additionally with imipramine, beginning on the eighth day of corticosterone administration. Hippocampal slices were prepared 48 h after the last drug administration. 5-HT1A and 5-HT4 receptor-mediated effects on CA1 population spike amplitude were measured. While repeated corticosterone attenuated the inhibitory effect of 5-HT1A receptor activation by 8-OH-DPAT and enhanced the excitatory effect of 5-HT4 receptor activation by zacopride, imipramine treatment of naïve rats resulted in opposite changes. In the corticosterone plus imipramine group, the effect of 8-OH-DPAT and zacopride were not different from control, indicating that corticosterone-induced adaptive changes in the reactivity of 5-HT1A and 5-HT4 receptors were reversed by imipramine treatment.

Differential effects of repeated imipramine on hippocampal responsiveness to adenosine and serotonin.

Imipramine-induced enhancement of the inhibitory action of 5-HT(lA) receptor activation in hippocampal pyramidal neurons has been attributed to alterations in the transduction mechanism that involves G protein-dependent opening of K(+) channels. Postsynaptic 5-HT(lA) and adenosine Al receptors may share that transduction pathway. We investigated the influence of repeated imipramine administration on 5-HT(lA) and adenosine A1 receptor-mediated effects in rat hippocampal slices. Repeated imipramine selectively enhanced the postsynaptic effects of 5-HT(1A) receptor activation, including hyperpolarization and reduction of input resistance of neurons and reduction of the population spike amplitude. In contrast, after imipramine treatment only the presynaptic effect of adenosine receptor agonists, a decrease of the field excitatory postsynaptic potential, was enhanced. The data demonstrate that alterations in the presumed common transduction mechanism that was postulated for the 5-HT(lA) and adenosine A1 receptor-mediated activation of K(+) channels are not involved in the effect of repeated imipramine administration.